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Review
. 2022 Sep 27:12:975261.
doi: 10.3389/fonc.2022.975261. eCollection 2022.

Role of myeloid-derived suppressor cells in the formation of pre-metastatic niche

Guoqi Ya  1 , Weihong Ren  2 , Rui Qin  1 , Jiao He  1 , Shuo Zhao  2
Affiliations
Review

Role of myeloid-derived suppressor cells in the formation of pre-metastatic niche

Guoqi Ya et al. Front Oncol. .

Abstract

Metastasis is a complex process, which depends on the interaction between tumor cells and host organs. Driven by the primary tumor, the host organ will establish an environment suitable for the growth of tumor cells before their arrival, which is called the pre-metastasis niche. The formation of pre-metastasis niche requires the participation of a variety of cells, in which myeloid-derived suppressor cells play a very important role. They reach the host organ before the tumor cells, and promote the establishment of the pre-metastasis niche by influencing immunosuppression, vascular leakage, extracellular matrix remodeling, angiogenesis and so on. In this article, we introduced the formation of the pre-metastasis niche and discussed the important role of myeloid-derived suppressor cells. In addition, this paper also emphasized the targeting of myeloid-derived suppressor cells as a therapeutic strategy to inhibit the formation of pre-metastasis niche, which provided a research idea for curbing tumor metastasis.

Keywords: circulating tumor cells; immunosuppression; myeloid-derived suppressor cells; pre-metastatic niche; targeted therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The formation of PMN. (A) Vascular leakage is the initial marker of PMN formation. Cytokines such as COX2, MMP1 and MMP2 secreted by primary tumors increase the permeability of endothelial cells and help the exudation of tumor cells. (B) Under the induction of hypoxic microenvironment and TDSFs, MDSCs and other immune cells are recruited to PMN, creating an excellent immune microenvironment for tumor cells. (C) At the same time, the ECM in the host organ began to change, providing a good environment for the growth of tumor cells. The accumulation of fibronectin and the crosslinking of collagen I provide a platform for the adhesion of MDSCs. At the same time, MMPs promote angiogenesis and contribute to tumor cells intrusion. In addition, some cytokines secreted by MDSCs also contribute to the remodeling of ECM. (D) Tumor cells arriving at the host organ will enter a dormant state, which is regulated by cytokines secreted by tumor cells and MDSCs. When tumor cells wake up, they continue to grow. (E) The formation of the PMN is a comprehensive result of vascular leakage, MDSCs recruitment and ECM remodeling. The tumor cells shed from the primary site and colonized the host organ, eventually forming a distant metastasis.
Figure 2
Figure 2
Immunological effects of MDSCs. (A) MDSCs consume L-arginine and L-cysteine required for T cell activation by expressing Arg-1 and ingesting cystine. (B) MDSCs produce reactive oxygen species by expressing Arg-1, iNOS and NOX. Different components of reactive oxygen species have inhibitory effects on T cells and B cells. (C) Under the induction of S100A9 and HIF-1α, the expression levels of PD-L1 on MDSCs increased. High levels of PD-L1 combined with PD-1 on T cells induced T cell apoptosis. (D) TGF-β Induce MDSCs to produce CD39 and CD73, which can induce the conversion of ATP to adenosine. The presence of adenosine inhibits the activation and proliferation of T cells. (E) In addition to inhibiting T cells, MDSCs can also regulate other immune cells to protect tumor cells and establish immune microenvironment. MDSCs inhibit the killing effect of NK cells by producing TGF-β and NO) they weakened the antigen-presenting function of DCs and macrophages by producing IL-10, and transformed M1 macrophages into M2 macrophages) they also secrete TGF-β and IL-10 up regulates the expression of FoxP3 in Tregs and induce the production of FoxP3+ Tregs.
Figure 3
Figure 3
Non immunological effects of MDSCs. (A) MDSCs promote EMT of tumor cells by producing IL-6, IL-10, TGF-β and VEGF, which makes tumor cells obtain high migration and invasion ability. When CTCs reach the host organ, MDSCs will induce CTCs to undergo MET, restore their epithelial phenotype and promote their proliferation. (B) MMP2, MMP9, VEGF and Ang-2 produced by MDSCs effectively increase the permeability of blood vessels and are conducive to the extravasation of CTCs. At the same time, MDSCs combine with CTCs through VCAM-1 and NETs to form CTC/MDSC clusters, which promote the survival and extravasation of CTCs. (C) MDSCs promote angiogenesis in PMN by producing cytokines such as VEGF, MMP9, TGF-β and FGF-2. In addition, MDSCs derived exosomes miR-126a and miR-210 also induce angiogenesis.
Figure 4
Figure 4
Treatment strategies for MDSCs. (A) Inhibit the differentiation of MDSCs. (B) Inhibit the accumulation of MDSCs. (C) Inhibit the function of MDSCs.
See this image and copyright information in PMC

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